In the treatment of hypertension, it is essential to maintain blood pressure within a normal range rather than just control the symptoms thereof, thereby preventing life-threatening diseases such as stroke, heart failure, and coronary heart diseases (e.g., myocardial infarction), and cardiovascular complications such as renal failure. Since long-term administration of an antihypertensive drug is required for controlling blood pressure, selection of the drug should be made carefully. Further, advanced therapy using a combination of two or more drugs having pharmacological actions different from each other makes it possible to improve preventive or therapeutic effects, while reducing side effects arising from the long-term administration of a drug by lowering the amounts of individual drugs.
Antihypertensive drugs commonly used may be divided into three major categories such as diuretics, sympatholytics and vasodilators based on their action mechanisms. Vasodilators, widely prescribed antihypertensive drugs, may be further divided into several groups such as angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers and calcium channel blockers based on their pharmacological actions.
Amlodipine is the generic name for 3-ethyl-5-methyl-2-(2-aminoethoxy-methyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridine dicarboxylate, and amlodipine besylate is currently marketed as Norvasc®. Amlodipine blocks calcium channels, and is used for the treatment of cardiovascular disorders such as angina, hypertension and congestive heart failure.
Losartan is the generic name for 2-butyl-4-chloro-1-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1H-imidazol-5-methanol, which has been disclosed in U.S. Pat. Nos. 5,608,075; 5,138,069; and 5,153,197, etc. Losartan potassium is currently available as Cozaar®. Losartan blocks the binding of angiotensin II, a vasoconstrictor, to its receptor. It is used for treating hypertension, heart failure, ischemic peripheral circulation disorder, myocardial ischemia (angina pectoris), diabetic neuropathy and glaucoma, and also used for preventing the progression of heart failure post-myocardial infarction.
The present inventors found that a combined formulation of amlodipine and losartan having two distinct pharmacological action mechanisms is useful for the treatment of hypertension, and have conducted intensive studies on such a combined formulation. However, when the combined formulation of amlodipine and losartan was prepared, undesirable gelation of losartan was observed. More particularly, losartan is easily dissolved in purified water or at a relatively high pH (e.g., pH 6.8, etc.) showing good dissolution patterns, but it is very slowly dissolved at a low pH (e.g., pH 1.2 or 2.0) because of its gelation. As such, in the combined formulation of amlodipine and losartan, amlodipine may also be trapped in the losartan gel due to the gelation of losartan, resulting in a decrease in dissolution rate.
An oral formulation generally undergoes disintegration and dissolution in stomach, which has low pH contents. Accordingly, a low dissolution rate of an active ingredient at a low pH (e.g., pH 1 or 2) can significantly affect its bioavailability.
In addition, considering that the gastric pH of a normal adult varies widely in a range of 1.0 to 3.5 and Cmax of losartan after food ingestion is reduced by about 10% (PDR), development of a formulation capable of maintaining a relatively constant dissolution rate despite such variations of gastric pH is needed to achieve maximum effect of a drug by maximizing drug absorption and minimizing variations in drug absorption within an individual or among individuals. In this context, in case of a combined formulation of amlodipine and losartan, a high amount of at least one type of disintegrant is required to develop a formulation which shows little differences in dissolution rate at a normal range of gastric pH variations, and shows high dissolution rate by preventing the gelation of losartan under low pH conditions. However, a formulation using a relatively high content of disintegrant may have problems in its storage stability due to the water absorbing property of the disintegrant. More particularly, upon exposure to moisture, a pharmaceutical composition using a high amount of disintegrant is likely to show changes in its property and a decrease in its efficacy. Thus, there has been a need for developing a pharmaceutical composition with improved storage stability, to prevent the decrease in dissolution rate.
The present inventors have therefore endeavored to develop a combined formulation comprising losartan and amlodipine, for the prevention or treatment of cardiovascular disorders, in the form of a solid formulation which has improved dissolution rate, stability and therapeutic efficacy. As a result, the present inventors have found that, by employing a disintegrant and a coating agent in a composition at a specific ratio, low dissolution rate arising from the losartan gelation in an acidic environment can be significantly improved, while changes in the properties of the composition upon exposure to moisture can be prevented, affording efficient delivery of its active ingredients and improved storage stability.
In the present patent application, reference will be made to articles and patent documents along with citations thereto. The contents of the articles and patent documents are herein incorporated by reference in their entireties, and thereby the level of technical field to which the present invention belong and the disclosure of the present invention are explained with more clarity.